MLH1 PROMOTER HYPERMETHYLATION IS ASSOCIATED WITH THE MICROSATELLITE INSTABILITY PHENOTYPE IN SPORADIC ENDOMETRIAL CARCINOMAS

Microsatellite instability (MSI) has been detected in endometrial carc inomas occurring in women affected by hereditary nonpolyposis colorect al carcinoma (HNPCC) as well as in 20% of presumably sporadic endometr ial tumors. While the MSI+ phenotype observed in endometrial tumors fr om HNPCC patients is attributed to germ line mutations in mismatch rep air (MMR) genes, somatic mutations of known MMR genes are infrequent i n MSI+ sporadic endometrial carcinomas, Recently, cytosine methylation of the MLH1 promoter region has been identified in a subset of MSI+ c olon primary carcinomas and cell lines. We studied the MLH1 and MSH2 p romoter methylation status in 29 presumably sporadic uterine endometri oid carcinomas (UECs), which had previously been characterized for the MSI phenotype and a subset for DNA MMR gene mutational status. We fou nd that 13 (45%) of 29 cases of EC were hypermethylated in the 5' CpG island of MLH1. Hypermethylation of MSH2 was not observed, MLH1 was hy permethylated in 12 (92%) of 13 MSI+ tumors, while only 1 (6%) of 16 M SI- tumors (Fischer's exact test P < 0.0001). Other tumor types we tes ted did not demonstrate MLH1 promoter hypermethylation, Our data sugge st that hypermethylation of MLH1, but not of MSH2, is associated with the MSI phenotype in sporadic endometrial carcinomas.